Pancreatic adenocarcinoma is the most lethal pancreatic tumor. Currently surgical resection is the only therapy which can provide a 5 year survival. However, less than 15% of patients diagnosed with pancreatic adenocarcinoma will be fortunate enough to undergo surgical resection. Even with a complete surgical resection and adjuvant chemotherapy the actual 5 year survival is only 12%. These clinical findings highlight the need of biomarkers to identify this small fraction of patients and develop alternative and innovative therapeutic strategies. To address these needs, this proposal will test the hypothesis that the expression level of the costimulatory molecule B7-H3 in primary pancreatic carcinoma lesions correlates with clinical response to combinatorial surgery and adjuvant therapy, and that a tumor-restricted determinant of B7-H3 represents an appropriate target to apply antibody-based immunotherapy for this disease. This hypothesis stems from the following lines of evidence in the literature and our own results: i) the level of B7-H3 expression in hypopharyngeal carcinoma, non-small-lung carcinoma, renal cell carcinoma and prostate carcinoma is associated with the clinical course of the disease, ii) the B7-H3-specific mAb 376.96, generated in our laboratory, recognizes a determinant which is expressed with high frequency on malignant human tumor cells, including pancreatic carcinoma cell lines and surgically removed pancreatic carcinoma lesions, but has a very restricted distribution in normal tissues, and iii) mAb 376.96 mediates cell dependent cytotoxicity of human malignant tumor cells in antibody dependent cell-mediated cytotoxicity (ADCC) assays. To this end, we will measure the B7-H3 expression level in primary pancreatic carcinoma lesions with well- defined clinical information and correlate the results of this immunohistochemical analysis with the clinical responses. Furthermore, we will test the hypothesis that the extent of lysis and the anti-tumor effects mediated by mAb 376.96, like those mediated by other tumor antigen-specific mAb, such as CD20- EGFR- and HER2- specific mAb, are influenced by the polymorphism of the Fc? receptor, Fc?RIIIa, expressed by NK cells. The latter are the main effector cells. The information resulting from these studies will i) contribute to define the clinical significance of B7-H3 expression levels in primary pancreatic carcinoma lesions, and ii) represent a useful background to design antibody-based immunotherapeutic strategies to be tested in phase I trials in patients with pancreatic adenocarcinoma. PUBLIC HEALTH RELEVANCE: There is an urgent need not only for effective therapeutic strategies to improve pancreatic adenocarcinoma patients'survival, but also for biomarkers to identify patients who are likely to benefit from the combination of surgical and adjuvant chemotherapy. To address these needs, this proposal will test the hypothesis that B7-H3, a member of the B7 immune costimulatory molecule family, represents a novel prognostic biomarker and a valid target to apply antibody-based immunotherapy in patients with pancreatic adenocarcinoma.